Diabetes mellitus develops spontaneously in mature Macaca nigra. The earliest hormonal and islet morphological alterations can be identified and studied before development of the abnormal glycemic criteria characteristic of diabetes. Altered intraislet secretory cell interactions lead to hormonal changes. Normal control mechanisms will be delineated and aberrations in islet hormone responses assessed by perfusion of the pancreas with various secretagogues in monkeys of different metabolic states. The effectiveness of preventive therapy regimens will be assessed in monkeys in the stages before overt diabetes. One group will receive tolbutamide, another group will be given insulin injections, and the third group will receive no therapy. Effective therapy should prevent or delay changes in glucagon and insulin levels and secretion, islet morphological deterioration, amyloid deposition, glycemic changes and secondary complications. Islets in pancreatic biopsy sections taken from monkeys of varied metabolic states will be examined to quantify alterations in secretory cell numbers and amounts of amyloid. Antibody involvement in the amyloidotic islet lesion will be assessed. The hormonal and islet morphological changes preceding diabetes can be detected in Macaca nigra long before similar stages in human beings. Monkeys can be intensively monitored, experimentally manipulated, and effectiveness of therapy assessed in ways not possible with human beings. Relationships between the hormonal and morphological aspects of the islet lesion can be identified and correlated with each other and with the development of diabetes. Data from Macaca nigra will be useful in determining whether identification and treatment of the hormonal and metabolite abnormalities preceding glycemic changes could prevent overt diabetes and its complications in humans.